Accurate Determination of Cavitand Binding Free Energies via Unrestrained Advanced Sampling

Calculation of binding free energies, which characterize the stability and specificity of molecular interactions (e.g., drug formulations), has been established as an important application of modern computational chemistry. Though several methodologies currently exist within the literature, there is always a need for improvements in speed and accuracy that allow for efficient and accurate chemical screening. In this paper we explore the application of an unrestrained advanced sampling method, adaptive biasing force (ABF), to the calculation of standard binding free energies for a set of molecular host–guest systems for which the binding free energy is well-known: the cucurbit[7]­uril-hosted systems utilized in the HYDROPHOBE challenge [Assaf et al. J. Phys. Chem. B 2017, 121, 11144−11162]. We demonstrate that the use of the ABF advanced sampling method yields values systematically closer to experiment, with a lower uncertainty in the calculation, than thermodynamic integration and restrained sampling techniques commonly used in the literature. We hypothesize that this is due to the algorithm’s ability to drive multiple binding and dissociation events through applied bias forces. These results show the promise of unrestrained advanced sampling methods along well-defined reaction coordinates to the calculation of binding energies in host–guest systems.